PDGFRB Mutations Research Articles

Mutated Ephrin Receptor Genes in Non‐Small Cell Lung Carcinoma and Their Occurrence with Driver Mutations—Targeted Resequencing Study on Formalin‐Fixed, Paraffin‐Embedded Tumor Material of 81 Patients

Non-small cell lung carcinoma (NSCLC) is the most common subtype of lung cancer. The oncogenic potential of receptor tyrosine kinases (RTKs) is widely known and they are potential targets for tailored therapy. Ephrin receptors (Ephs) form the largest group of RTKs. Nevertheless, Ephs are not widely studied in NSCLC so far. The aim of our study was to investigate novel mutations of Eph genes (EPHA1-8, EPHB1-4, EPHB6) and their association with clinically relevant mutations in BRAF, EML4-ALK, EGFR, INSR, KDR, KRAS, MET, PDGFRA, PDGFRB, PIK3, PTEN, RET, and TP53 in NSCLC patients. Targeted resequencing was conducted on 81 formalin-fixed, paraffin-embedded NSCLC tumor specimens. We analyzed missense and nonsense mutations harbored in the coding regions of the selected genes. We found 18 novel mutations of Ephs in 20% (16 of 81) of the patients. Nearly half of these mutations occurred in the protein kinase domain. The mutations were not mutually exclusive with other clinically relevant mutations. Our study shows that Ephs are frequently mutated in NSCLC patients, and occur together with other known mutations relevant to the pathogenicity of NSCLC.

Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification

Idiopathic basal ganglia calcification is characterized by mineral deposits in the brain, an autosomal dominant pattern of inheritance in most cases and genetic heterogeneity. The first causal genes, SLC20A2 and PDGFRB, have recently been reported. Diagnosing idiopathic basal ganglia calcification necessitates the exclusion of other causes, including calcification related to normal ageing, for which no normative data exist. Our objectives were to diagnose accurately and then describe the clinical and radiological characteristics of idiopathic basal ganglia calcification. First, calcifications were evaluated using a visual rating scale on the computerized tomography scans of 600 consecutively hospitalized unselected controls. We determined an age-specific threshold in these control computerized tomography scans as the value of the 99th percentile of the total calcification score within three age categories: <40, 40-60, and >60 years. To study the phenotype of the disease, patients with basal ganglia calcification were recruited from several medical centres. Calcifications that rated below the age-specific threshold using the same scale were excluded, as were patients with differential diagnoses of idiopathic basal ganglia calcification, after an extensive aetiological assessment. Sanger sequencing of SLC20A2 and PDGFRB was performed. In total, 72 patients were diagnosed with idiopathic basal ganglia calcification, 25 of whom bore a mutation in either SLC20A2 (two families, four sporadic cases) or PDGFRB (one family, two sporadic cases). Five mutations were novel. Seventy-one per cent of the patients with idiopathic basal ganglia calcification were symptomatic (mean age of clinical onset: 39 ± 20 years; mean age at last evaluation: 55 ± 19 years). Among them, the most frequent signs were: cognitive impairment (58.8%), psychiatric symptoms (56.9%) and movement disorders (54.9%). Few clinical differences appeared between SLC20A2 and PDGFRB mutation carriers. Radiological analysis revealed that the total calcification scores correlated positively with age in controls and patients, but increased more rapidly with age in patients. The expected total calcification score was greater in SLC20A2 than PDGFRB mutation carriers, beyond the effect of the age alone. No patient with a PDGFRB mutation exhibited a cortical or a vermis calcification. The total calcification score was more severe in symptomatic versus asymptomatic individuals. We provide the first phenotypical description of a case series of patients with idiopathic basal ganglia calcification since the identification of the first causative genes. Clinical and radiological diversity is confirmed, whatever the genetic status. Quantification of calcification is correlated with the symptomatic status, but the location and the severity of the calcifications don't reflect the whole clinical diversity. Other biomarkers may be helpful in better predicting clinical expression.

A Recurrent PDGFRB Mutation Causes Familial Infantile Myofibromatosis

Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor β (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-β promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-β as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-β in aggressive life-threatening familial forms of the disease.

Mutations in PDGFRB Cause Autosomal-Dominant Infantile Myofibromatosis

Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment.

Novel t(5;19) Translocation in a Patient with PDGFRB Associated Chronic Leukemia: Implications for Treatment Strategy

Myeloproliferative disorders are variable disorders, based on the genetic abnormality present and the cell line progenitors that are affected. In this case, we discuss a novel gene translocation in the subset of PDGFRB mutations, first seen with prominent hyperbasophilia. This case demonstrates the possibility for lower therapeutic doses of imatinib mesylate than previously reported, in order to control leukocyte counts and reverse the genetic mutation.

Concurrent acute myeloid leukemia and T lymphoblastic lymphoma in a patient with rearranged PDGFRB genes

Concurrent hematologic malignancies are relatively rare. We encountered a case of concurrent acute myeloid leukemia (AML) and T lymphoblastic lymphoma. The bone marrow chromosome analysis showed the karyotype 46, XY, t(5;12)(q33;p13), which indicated presence of PDGFRB gene translocations. Therefore, this disease belongs to the new WHO category of myeloid and lymphoid neoplasms with abnormalities in PDGFRA, PDGFRB and FGFR1 genes. Although such genetic mutations are prone to multi-lineage differentiation, the present case is in fact the first report of concurrent AML and T lymphoblastic lymphoma involving PDGFRB mutations. The patient was treated with cytarabine and daunomycin in combination with high dose dexamethasone. Allogeneic stem cell transplantation was performed after successful remission induction for both entities. The patient eventually died of chronic graft-versus-host-disease related infection. Based on such an experience, we suggest the decision of stem cell transplantation should be weighed carefully against the risks, especially when tyrosine kinase inhibitors are safe and potentially effective in dealing with such entities.

Concurrent acute myeloid leukemia and T lymphoblastic lymphoma in a patient with rearranged PDGFRB genes

Concurrent hematologic malignancies are relatively rare. We encountered a case of concurrent acute myeloid leukemia (AML) and T lymphoblastic lymphoma. The bone marrow chromosome analysis showed the karyotype 46, XY, t(5;12)(q33;p13), which indicated presence of PDGFRB gene translocations. Therefore, this disease belongs to the new WHO category of myeloid and lymphoid neoplasms with abnormalities in PDGFRA, PDGFRB and FGFR1 genes. Although such genetic mutations are prone to multi-lineage differentiation, the present case is in fact the first report of concurrent AML and T lymphoblastic lymphoma involving PDGFRB mutations. The patient was treated with cytarabine and daunomycin in combination with high dose dexamethasone. Allogeneic stem cell transplantation was performed after successful remission induction for both entities. The patient eventually died of chronic graft-versus-host-disease related infection. Based on such an experience, we suggest the decision of stem cell transplantation should be weighed carefully against the risks, especially when tyrosine kinase inhibitors are safe and potentially effective in dealing with such entities.

Cyclooxygenase-2 and Platelet-Derived Growth Factor Receptors as Potential Targets in Treating Aggressive Fibromatosis

To explore the molecular bases of potential new pharmacologic targets in aggressive fibromatosis (desmoid tumor). Tumor specimens from 14 patients surgically treated for aggressive fibromatosis (6 familial adenomatous polyposis and 8 sporadic cases), analyzed for adenomatous polyposis coli (APC) and CTNNB1 (beta-catenin) mutations, were further investigated for beta-catenin, cyclooxygenase-2 (COX-2), platelet-derived growth factor (PDGF) receptor alpha (PDGFRA)/PDGF receptor beta (PDGFRB), their cognate ligands (PDGFA and PDGFB), and KIT using a comprehensive immunohistochemical, biochemical, molecular, and cytogenetic approach. No CTNNB1 (beta-catenin) mutations were found in the familial adenomatous polyposis patients, but previously reported activating mutations were found in six of the eight sporadic patients. All of the cases carrying an altered WNT pathway showed nuclear and cytoplasmic immunoreactivity for beta-catenin, whereas beta-catenin expression was restricted to the cytoplasm in the sporadic patients lacking CTNNB1 mutations. COX-2 protein and mRNA overexpression was detected in all 14 cases, together with the expression and phosphorylation of PDGFRA and PDGFRB, which in turn paralleled the presence of their cognate ligands. No PDGFRB mutations were found. The results are consistent with PDGFRA and PDGFRB activation sustained by an autocrine/paracrine loop. Aggressive fibromatosis is characterized by WNT/oncogene pathway alterations triggering COX-2-mediated constitutive coactivation of PDGFRA and PDGFRB, and may therefore benefit from combined nonsteroidal anti-inflammatory drug + tyrosine kinase inhibitor treatment.